The use of living cells in culture for biomedical research was first introduced by Dr. Otto Warburg in the 1920's. Today, this technique enables scientists to model specific biochemical or physiological properties of cells under defined and reproducible conditions. Cell culture technology has made possible the study of many diseases independent of either patient or animal models. The obvious advantage of this methodology is that a variety of experiments can be performed while avoiding the moral dilemma of using human beings or animals as research tools.
Currently, both human and animal cell lines serve as surrogates for living organisms in screening the efficacy or toxicity of pharmaceuticals, agri-chemicals, and nearly all chemicals used in consumer products. The rapidly proliferating area of in vitro alternatives to animal testing utilizes cell culture techniques to model such toxic responses as skin and eye irritation.
While cell culture technology has given science the ability to perform research not possible at the beginning of this century, it has significant inherent limitations. As a result, cell culture methods have not superseded research on humans or animals as the ultimate predictor of biological response. One limitation is that current techniques of exposing and dosing cell cultures yield results which lack a physiologically based foundation. As a result, such exposure methods are not equivalent to the physiologic pattern of exposure encountered by cells in a living being. More particularly, present cell culture techniques are not able to duplicate the metabolism of dose regimens in living organisms where concentrations are greatest immediately following exposure and decline until the cell culture is subsequently exposed to that substance. As a result, it is not possible to determine whether pharmacological changes or damage induced at peak concentrations will be reversed as concentration falls and the cell returns to a pre-exposure status.
Within living beings, concentration and time interact to influence the intensity and duration of a desired pharmacologic response or toxic manifestation. With respect to exposure to toxic substances, many types of cells undergo a biotransformation reaction to protect them from chemical damage. For example, cells, which utilize glutathione ("GSH") to protect themselves against chemical damage, may deplete GSH reserves when exposed to high concentrations of toxic chemicals. As a result, if subsequent exposures occur before repletion of GSH stores, the cell will manifest a toxic response. However, if there is sufficient time for replenishment of GSH reserves, no toxicity will develop. Thus, exposure frequency is as critical a determinant of cellular toxicity as the amount of exposure to a chemical. This characteristic waxing and waning of chemical exposure and resultant cellular responses cannot be mathematically stimulated based on the results of a cell culture experiment performed with static exposure concentrations.